Download - EFC.ppt
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165.000 –
415.000/L
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HEMOSTAZĂ FIBRINOLIZĂ
ECHILIBRU METABOLIC
ECHILIBRU
ECHILIBRUL FLUIDO-COAGULANT
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HEMOSTAZA ↓
FIBRINOLIZA ↑
DEZECHILIBRU
SINDROAME HEMORAGIPARE
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HEMOSTAZA ↑
FIBRINOLIZA ↓
DEZECHILIBRU
SINDROAME TROMBOEMBOLICE
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HEMOSTAZA
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ECHILIBRUL FLUIDO-COAGULANT
HEMOSTAZA
FIBRINOLIZA
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ECHILIBRUL FLUIDO-COAGULANT
HEMOSTAZA
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HEMOSTAZA
ETAPA (TIMPUL) VASCULARĂ
ETAPA (TIMPUL) PLACHETARĂ
ETAPA (TIMPUL) PLASMATICĂ
HEMOSTAZA PRIMARĂ- Formarea dopului alb (plachetar)
HEMOSTAZA SECUNDARĂ (COAGULAREA)- Formarea dopului roşu (fibrină)
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HEMOSTAZA
ETAPA (TIMPUL) VASCULARĂ
ETAPA (TIMPUL) PLACHETARĂ
ETAPA (TIMPUL) PLASMATICĂ
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HEMOSTAZA – ETAPA (TIMPUL) VASCULARĂ
(minute, ore)
• VASOCONSTRICŢIA CMN din pereţii vasculari
→↓ fluxului sanguin local
MECANISME
- spasm miogenic local – generat de injuria peretelui vascular
- autacoizi locali – TxA2 (origine: ţesuturile traumatizate, plăcuţe)
- reflexe nervoase – iniţiate de durere/alţi stimuli locali
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HEMOSTAZA
ETAPA (TIMPUL) VASCULARĂ
ETAPA (TIMPUL) PLACHETARĂ
ETAPA (TIMPUL) PLASMATICĂ
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HEMOSTAZA – ETAPA (TIMPUL) PLACHETARĂ
(minute, ore)
• PLĂCUŢELE SANGUINE (TROMBOCITELE)
- Fragmente celulare 1 – 4 MEGACARIOCITE
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HEMOSTAZA – ETAPA (TIMPUL) PLACHETARĂ
(minute, ore)
• PLĂCUŢELE SANGUINE (TROMBOCITELE)
- Fragmente celulare 1 – 4 MEGACARIOCITE
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TROMBOCITOPOIEZA
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I. CELULA STEM HEMATOPOIETICA PLURIPOTENTA (HSC)
→ DOUA TIPURI DE CELULE STEM MULTIPOTENTE
• CELULA STEM MULTIPOTENTA MIELOIDA (CFU-M)
(CFU-GEMM)
• CELULA STEM MULTIPOTENTA LIMFOIDA (CFU-L)
II.
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HSC
CFU-M (CFU-GEMM) CFU-L
CFU-E PROGENITORI Lf T, Lf B
CFU-GM
CFU-M
CELULE ORIENTATE, COMMITED , PROGENITOARE
CELULE STEM
CELULE PRECURSOARE
• PROMEGACARIOBLAST
• MEGACARIOBLAST
• MEGACARIOCITUL BAZOFIL
• MEGACARIOCITUL GRANULAR
• MEGACARIOCITUL TROMBOCITOGEN
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HEMOSTAZA – ETAPA (TIMPUL) PLACHETARĂ
(minute, ore)
• PLĂCUŢELE SANGUINE (TROMBOCITELE)
- Fragmente celulare 1 – 4 MEGACARIOCITE
- 2/3 circulante: 165.000 – 415.000 / L (mm3) (L-6)
- 1/3 sechestrate la nivel splenic (compartiment de rezervă)
- T ½ = 8 – 12 zile (eliminate de SMM tisular/splenic)
- Anucleate → nu se pot reproduce
→ nu pot resintetiza anumite componente structurale
- Membrana – glicocalix – rol important in ech. FC
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HEMOSTAZA – ETAPA (TIMPUL) PLACHETARĂ
• PLĂCUŢELE SANGUINE (TROMBOCITELE)
CARACTERISTICI
- Proteine contractile - actină
- miozină
- trombostenină
- F. reziduale de RE + ap. Golgi – sinteză (enzime)
- ↑↑↑ Ca2+ ic
- Mitocondrii (ATP, ADP)
- Sisteme enzimatice de metabolizare a ac. arahidonic
- FSF (fibrin-stabilizing factor)
- PDGF (platelet-derived growth factor)
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PARTICIPAREA PLACUŢELOR LA HEMOSTAZĂ :
- HEMOSTAZA PRIMARĂ
- Hemostaza secundară (coagularea) : FP4
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-V
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HEMOSTAZA
ETAPA (TIMPUL) VASCULARĂ
ETAPA (TIMPUL) PLACHETARĂ
ETAPA (TIMPUL) PLASMATICĂ
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FIZIOLOGIA COAGULARII
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1 11
2
CE
CI
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Factor Nume
I Fibrinogen
II Protrombina
III Factorul tisular sau tromboplastina
IV Calciu
V Proaccelerina (Factorul labil)
VII Proconvertina (Factorul stabil)
VIII Factorul antihemofilic A, Globulina antihemofilica A
IX Factorul antihemofilic B, Componentul tromboplastinic, Factorul Christmas
X Factorul Stuart-Prower
XI Factorul antihemofilic C, Antecesorul tromboplastinei plasmatice, Factorul Rosenthal
XII Factorul Hageman
XIII Factorul de stabilizare a fibrinei, Factorul Laki-Lorand
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Secondary Hemostasis: Coagulation Factors oProcoagulants a.k.a coagulation factors a.k.a clotting factorsoMajority are glycoproteinsoMajority are synthesized in the liver
Few synthesized in monocytes, endothelia, and mekaryocytes
oEight circulate as zymogensoFour are cofactorsoCategorized as substrates, cofactors, or enzymes
Nomenclature
oRoman numeralso“a” indicates active formoI, II, III, IV occasionally identified by roman numeraloThere’s no VI assignedoPLT factor 3, Prekallikrein, & HMWK are not assigned roman numerals
Physical Properties Groupings
FactorCommon Name
FunctionPlasma Concentration
I* Fibrinogen Fibrin precursor 200 – 400 mg/dL
II* Prothrombin Thrombin precursor 10 mg/dL
III* Tissue Factor Cofactor none
IV* Ionized calcium Essential Mineral 8 – 10 mg/dL
V Labile Factor Cofactor 1 mg/dL
VII Stable Factor Serine Protease 0.05 mg/dL
VIII Antihemophilic Factor
Cofactor 0.01 mg/dL
vWF Von Willebrand Factor
VIII Carrier & PLT Adhesion
1 mg/dL
IX Christmas Factor Serine Protease 0.3 mg/dL
X Stuart-Prower Factor
Serine Protease 1 mg/dL
XI Plasma Thromboplastin Antecedent Serine Protease
0.5 mg/dL
XII Hageman Factor Serine Protease 3 mg/dL
XIII Fibrin-stabilizing Factor
Transglutaminase 2 mg/dL
Prekallikrein Fletcher Factor Serine Protease 35 – 50 g/dL
HMWK Fitzgerald Factor Cofactor 5 mg/dL
PLT Factor 3 Phosphotidyl Serine Assembly Molecule none
*Customarily identified by name rather than Roman numeral.
Contact Factors
Vitamin-K Dependent
Thrombin-Sensitive
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PROBLEME
• DEFICITUL DE HMWK, PK, F XII :
aPTT
clinic nu există manifestări hemoragipare
• DEFICITUL DE F XI :
mare heterogenitate a manifestărilor hemoragipare
• HEMOFILIA DE TIP A ŞI B :
hemoragii grave, DEŞI rămâne intactă coagularea extrisecă
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PROBLEME
De ce doua moduri de activare a cascadei coagularii????
Sunt cele doua cai (CI si CE) redundante? de ce deficitul - de F VII (CE)
- de F VIII, IX, XI (CI)determina sindroame hemoragipare GRAVE???
Care este: - rolul - limitele - importanta - semnificatiafiecareia dintre cele doua cai de activare a coagularii?
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TFPI = Tissue Factor Inhibitory Pathway
12 – 15 s.35 – 40 s.
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FC vit. K-dependenţi : II, VII, IX, X, PC, PS
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ECHILIBRUL FLUIDO-COAGULANT
HEMOSTAZA
FIBRINOLIZA
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FIZIOLOGIA FIBRINOLIZEI
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ANOMALII ALE ECHILIBRULUI FLUIDO-COAGULANT
CAUZE PLACHETARE
CAUZE VASCULARE
CAUZE PLASMATICE
AFECTAREA FIBRINOLIZEI
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SINDROAME HEMORAGIPARE DE CAUZĂ PLACHETARĂ
DEFECTE PLACHETARE :
• CANTITATIVE - TROMBOCITOPENII
• CALITATIVE
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SINDROAME HEMORAGIPARE DE CAUZA PLACHETARA
DEFECTE PLACHETARE :
• CANTITATIVE - TROMBOCITOPENII
• CALITATIVE
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I. Scăderea producţiei medulare de megacariociteInfiltrarea măduvei prin tumori, fibrozeInsuficienţă medulară – anemie aplastică, hipoplastică,
medicamente
II. Sechestrarea splenică a plachetelor circulanteHipertrofia splinei datorată infilrării tumoraleCongestia splinei datorată hipertensiunii portale
III. Distrugerea crescută a plachetelor circulante A. Distrugere nonimună
Proteze vasculare, valve cardiaceCoagulare intravasculară diseminatăSepticemieVasculită
B. Distrugere imunăAutoanticorpi anti antigenele plachetareAnticorpi asociaţi cu ingestia de medicamenteComplexe imune circulante – lupus eritematos sistemic,
agenţi virali, septicemii bacteriene
CAUZELE TROMBOCITOPENIILOR
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Medicamente potenţial trombocitopenice (1)
1. Agenţi chimioterapici (în special carboplatina, agenţii alchilanţi, antraciclinele, antimetaboliţii)
2. Antibiotice (sulfonamide, peniciline, cefalosporine)
3. Heparinele (incidenţa maximă în cazul heparinelor nefracţionate)
4. Medicamente de uz cadiovascular (diuretice tiazidice, rar inhibitorii enzimei de conversie)
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Medicamente potenţial trombocitopenice (2)Mecanisme de acţiune
1. SUPRESIA PRODUCŢIEI DE PLACHETE
• Medicamente mielosupresive- Severe: citozin-arabinozidă, daunorubicină- Moderate: ciclofosfamidă, busulfan, metotrexat,
6-mercaptopurină- Uşoare: alcaloizii de vinca
• Diuretice tiazidice
• Etanol
• Estrogeni
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SINDROAME HEMORAGIPARE DE CAUZA PLACHETARA
DEFECTE PLACHETARE :
• CANTITATIVE - TROMBOCITOPENII
• CALITATIVE
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Tulburări ale hemostazei primare prin defecte plachetare calitative
• Defecte ale adeziunii plachetareBoala von WillebrandSindromul Bernard-Soulier (absenţa sau disfuncţia GpIb/IX/V)
• Defecte ale agregării plachetareTrombastenia Glanzmann (absenţa sau disfuncţia GpIIb/IIIa)
• Defecte ale secreţiei plachetareScăderea activităţii ciclooxigenazeiMedicamente – aspirină, antiinflamatorii nesteroidieneCongenitalăDeficite ale depozitelor granulelorCongenitaleDobânditeUremie„Acoperiri“ plachetare (de exemplu penicilină sau paraproteine)
• Defect de coagulare plachetarSindromul Scott
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Clasificarea defectelor plachetare calitative (funcţionale)I. Tulburări ale adezivităţii
A. Ereditare 1. Sindromul Bernard-Soulier 2. Boala von Willebrand (BvW)B. Dobândite 1. Uremia 2. BvW dobândită
II. Tulburåri ale agregabilităţiiA. Ereditare 1. Trombastenia Glanzmann 2. AfibrinogenemiaB. Dobândite 1. Inhibarea produçilor de degradare ai fibrinei 2. Disproteinemii 3. Ingestia de medicamente – de exemplu, ticlopidină, anticorpi anti IIb/IIIa (Rheo Pro)
III Tulburåri ale eliberårii granulelorA. Ereditare 1. Albinismul oculo-cutanat (sindromul Hermansky-Pudlak) 2. Sindromul Chediak-Higashi 3. Deficitul izolat al granulelor dense (δ) 4. Sindromul plachetelor gri – deficitul combinat al granulelor α şi δB. Dobândite 1. Bypass cardiopulmonar 2. Afecţiuni mieloproliferative 3. Medicamente – aspirina şi alţi agenţi antiinflamatori nesteroidieni
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ANOMALII ALE ECHILIBRULUI FLUIDO-COAGULANT
CAUZE PLACHETARE
CAUZE VASCULARE
CAUZE PLASMATICE
AFECTAREA FIBRINOLIZEI
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PURPURE VASCULARE (NONTROMBOCITOPENICE)
• manifestări hemoragipare uşoare, cutaneo-mucoase
• există şi boli idiopatice ale peretelui vascular ce determină hemoragii severe şi disfuncţii de organ
• patogeneza - incomplet definită :
- lezarea endoteliului capilar
- anomalii ale matricei vasculare subendoteliale
- anomalii ale ţesutului conjunctiv extravascular
- formarea de vase anormale
• testele de screening ale hemostazei primare = N
(TS, nr. PL., teste calitative plachetare)
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PURPURE VASCULARE (NONTROMBOCITOPENICE)
• PURPURA TROMBOTICĂ TROMBOCITOPENICĂ (PTT)
• SD. HEMOLITIC UREMIC
• PURPURA HENOCH-SCHÖNLEIN
• AFECŢIUNI METABOLICE ŞI INFLAMATORII
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EXPLORAREA HEMOSTAZEI PRIMARE
TESTELE DE SCREENING :
• Timpul de sângerare - TS
• Numărarea plăcuţelor sanguine
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Differences in the Clinical Manifestations of Disorders of Primary and Secondary Hemostasis
Manifestations Defects of Primary Hemostasis (Platelet Defects)
Defects of Secondary Hemostasis (Plasma Protein Defects)
Onset of bleeding after trauma
Immediate Delayed (hours or days)
Sites of bleeding Superficial skin, mucous membranes, nose, gastrointestinal and genitourinary tracts
Deep (joints, muscle, retroperitoneum)
Physical findings Petechiae, ecchymoses Hematomas, hemarthroses
Family history Autosomal dominant Autosomal or X-linked recessive
Response to therapy
Immediate; local measures effective
Requires sustained systemic therapy
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Evaluation of Platelet FunctionBleeding timeModified Ivy methodSkin incision (time to stop bleeding)Global screen of platelet role in hemostasis
von Willebrand factor assaysvWF Ag (immunoassay of total vWF protein)vWF R:Cof (bioassay of vWF that measures ability of patient plasma to support agglutination of normal platelets in the presence of ristocetin)Factor VIII (coagulation assay of factor VIII bound and carried by plasma vWF)
Platelet aggregometryMeasures platelet aggregation in response to a panel of agonists, usually ADP, collagen, arachidonic acid, and epinephrine
Membrane glycoproteinsPresence of glycoproteins Ib-IX and IIb-IIIa can be measured using monoclonal antibodies and flow cytometry
Platelet granule contentDense granules (electron microscopy or uptake and retention of radiolabeled serotonin)Alpha granules (electron microscopy and/or immunoassays for platelet-associated proteins - vWF, fibrinogen, platelet factor four
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TULBURĂRI ALE ECHILIBRULUI FLUIDO-COAGULANT
CAUZE PLACHETARE
CAUZE VASCULARE
CAUZE PLASMATICE
AFECTAREA FIBRINOLIZEI
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EXPLORAREA HEMOSTAZEI SECUNDARE (COAGULAREA)
TESTE DE SCREENING :
•TCG – TC (aPTT)
•TIMPUL DE PROTROMBINĂ (QUICK) = PT
•TIMPUL DE TROMBINĂ
•FIBRINOGENEMIA
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Relationship between Secondary Hemostatic Disorders and Coagulation Test Abnormalities
Prolonged partial thromboplastin time (PTT)No clinical bleeding (factors XII, HMWK, PK)Mild or rare bleeding (factor XI)Frequent, severe bleeding (factors VIII and IX) Prolonged prothrombin time (PT)Factor VII deficiencyVitamin K deficiency - earlyWarfarin anticoagulant ingestion Prolonged PTT and PTFactor II, V, or X deficiencyVitamin K deficiency - lateWarfarin anticoagulant ingestion Prolonged thrombin time (TT)Mild or rare bleeding, afibrinogenemiaFrequent, severe bleeding, dysfibrinogenemiaHeparin-like inhibitors or heparin administration Prolonged PT and/or PTT not corrected with normal plasmaSpecific or nonspecific inhibitor syndromes Clot solubility in 5 M ureaFactor XIII deficiencyInhibitors or defective cross-linking Rapid clot lysisa2 plasmin inhibitor
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MECANISMELE FIZIOPATOLOGICE ALE
SINDROAMELOR HEMORAGIPARE
DE CAUZĂ PLASMATICĂ
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I. DEFECTE ALE COAGULĂRII (COAGULARE )• HEMOFILII : A (VIII); B(IX); C(XI)
• DEFICITE ALE ALTOR F.C. : V, X, VII, II
XII, HMWK, PK
A-; hipo-; disFb-genemii
Deficienţa F XIII
• DEFICITUL DE VIT. K
• CID
• AFECŢIUNI HEPATICE
II. DEFECTE DE FIBRINOLIZĂ (FIBRINOLIZĂ )
III. ANTICOAGULANŢI CIRCULANŢI
Con-ge-ni-tale
Dobândite
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I. DEFECTE ALE COAGULARII (COAGULARE )• HEMOFILII : A (VIII); B(IX); C(XI)
• DEFICITE ALE ALTOR F.C. : V, X, VII, II
XII, HMWK, PK
A-; hipo-; disFb-genemii
Deficienţa F XIII
• CID
• AFECŢIUNI HEPATICE
II. DEFECTE DE FIBRINOLIZĂ (FIBRINOLIZĂ )
III. ANTICOAGULANŢI CIRCULANŢI
Con-ge-ni-tale
Dobândite
• DEFICITUL DE VIT. K
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FC vit. K-dependenţi : II, VII, IX, X, PC, PS
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Dg. diferenţial : deficit de FPC / deficit de VK
TESTUL KOLLER
DEFICIT FPC• APTT / PT
DEFICIT DE VK• APTT / PT
Administrare de VK (i.m.)
8 – 12 ore
• APTT / PT (nu se corectează)
TEST KOLLER (-)
• APTT / PT = N (se corectează)
TEST KOLLER (+)
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I. DEFECTE ALE COAGULĂRII (COAGULARE )• HEMOFILII : A (VIII); B(IX); C(XI)
• DEFICITE ALE ALTOR F.C. : V, X, VII, II
XII, HMWK, PK
A-; hipo-; disFb-genemii
Deficienţa F XIII
• DEFICITUL DE VIT. K
• AFECŢIUNI HEPATICE
II. DEFECTE DE FIBRINOLIZĂ (FIBRINOLIZĂ)
III. ANTICOAGULANŢI CIRCULANŢI
Con-ge-ni-tale
Dobândite• CID
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Liberation of tissue factors
Obstetric syndromes (abruptio placentae, amniotic fluid embolism, retained dead fetus, second trimester abortion)
Hemolysis
Neoplasms, particularly mucinous adenocarcinomas, acute promyelocytic leukemia
Intravascular hemolysis
Fat embolism
Tissue damage (burns, frostbite, head injury, gunshot wounds)
SINDROMUL DE COAGULARE INTRAVASCULARA DISEMINATA - CAUZE
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SINDROMUL DE COAGULARE INTRAVASCULARA DISEMINATA - CAUZE
Endothelial damage Aortic aneurysm
Hemolytic uremic syndrome
Acute glomerulonephritis
Rocky Mountain spotted fever
Vascular malformation and decreased blood flow
Kasabach-Merritt syndrome
Infections Bacterial: staphylococci, streptococci, pneumococci, meningococci, gram-negative bacilli
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I. DEFECTE ALE COAGULĂRII (COAGULARE )• HEMOFILII A : (VIII); B(IX); C(XI)
• DEFICITE ALE ALTOR F.C. : V, X, VII, II
XII, HMWK, PK
A-; hipo-; disFb-genemii
Deficienţa F XIII
• DEFICITUL DE VIT. K
• CID
II. DEFECTE DE FIBRINOLIZĂ (FIBRINOLIZĂ )
III. ANTICOAGULANŢI CIRCULANŢI
Con-ge-ni-tale
Dobândite
• AFECŢIUNI HEPATICE
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Causes of Bleeding in Liver DiseaseAnatomic Factors- Portal hypertensionVaricesSplenomegaly and secondary thrombocytopenia- Peptic ulceration- GastritisHepatic Function Abnormalities- Decreased synthesis of procoagulant proteins: fibrinogen, prothrombin, factors V, VII, IX, X, XI- Decreased synthesis of coagulation inhibitors: protein C, protein S, antithrombin III- Impaired absorption and metabolism of vitamin K- Failure to clear activated coagulation proteins leading to:Disseminated intravascular coagulationSystemic fibrinolysisComplications of Therapy- Dilution of platelets and coagulation proteins from massive transfusions- Infusion of activated coagulation proteins in prothrombin complex concentrates- Bleeding from heparin; thrombosis from e-aminocaproic acid (EACA)
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I. DEFECTE ALE COAGULĂRII (COAGULARE )• HEMOFILII A (VIII); B(IX); C(XI)
• DEFICITE ALE ALTOR F.C. : V, X, VII, II
XII, HMWK, PK
A-; hipo-; disFb-genemii
Deficienţa F XIII
• DEFICITUL DE VIT. K
• CID
• AFECŢIUNI HEPATICE
III. ANTICOAGULANŢI CIRCULANŢI
Con-ge-ni-tale
Dobândite
II. DEFECTE DE FIBRINOLIZĂ (FIBRINOLIZĂ )
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CAUZELE HEMORAGIILOR GENERATE DE FIBRINOLOZA
• DEFICITUL DE α2 PLASMIN-INHIBITOR
• DEFICITUL DE PAI-1
!!! TESTE DE SCREENING ALE COAGULĂRII NORMALE!!!
DEFICITUL DE F XIII
- Sindroame hemoragipare cu teste normale de coagulabilitate
solubilitatea cheagului în uree 5M
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I. DEFECTE ALE COAGULĂRII (COAGULARE )• HEMOFILII : A (VIII); B(IX); C(XI)
• DEFICITE ALE ALTOR F.C. : V, X, VII, II
XII, HMWK, PK
A-; hipo-; disFb-genemii
Deficienţa F XIII
• DEFICITUL DE VIT. K
• CID
• AFECŢIUNI HEPATICE
II. DEFECTE DE FIBRINOLIZĂ (FIBRINOLIZĂ )
Con-ge-ni-tale
Dobândite
III. ANTICOAGULANŢI CIRCULANŢI
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TULBURĂRI ALE ECHILIBRULUI FLUIDO-COAGULANT
TROMBEMBOLISM
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I. DEFECTE ALE COAGULĂRII (COAGULARE )• DEFICITUL DE PROTEINĂ (C)
• DEFICITUL DE PROTEINĂ (S)
• DEFICITUL DE ANTITROMBINĂ III
• FACTORUL V LEIDEN
• MUTAŢIA GENEI PT
II. DEFECTE DE FIBRINOLIZĂ (FIBRINOLIZĂ )
III. ANTICOAGULANŢI CIRCULANŢI
Deficienţa unor inhibitori ai coagulării
• DISFIBRINOGENEMIE
• DEFICIT DE PLASMINOGEN
• DEFICIT DE tPA
• EXCES DE PAI
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I. Inherited
• Defective inhibition of coagulation factorsFactor V Leiden (resistant to inhibition by activated protein C)Antithrombin III deficiencyProtein C deficiencyProtein S deficiencyProthrombin gene mutation (G40210A)
• Impaired clot lysisDysfibrinogenemiaPlasminogen deficiencytPA deficiencyPAI-1 excess • Uncertain mechanismHomocystinuria - ? endothelial damage
AFECTIUNI TROMBOTICE – CAUZE (1)
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Prevalence of Coagulation Defects in Patients with Venous Thrombosis
Defect Prevalence, %
Factor V Leiden (Arg506Gln) R506 Q 12-40
Hyperhomocysteinemia 10-20
Prothrombin G20210A 6-18
Deficiencies of antithrombin III, proteins C and S 5-15
Antiphospholipid antibody syndrome 10-20
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Relationship Between Coagulation Defect and Site of Thrombosis
Abnormality Arterial Venous
Factor V Leiden R506 Q - +
Prothrombin G20210A - +
Antithrombin III - +
Protein C - +
Protein S - +
Homocysteinemia + +
Antiphospholipid antibodya + +
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II. Acquired
• Diseases or syndromesLupus anticoagulant/anticardiolipin antibody syndromeMalignancyMyeloproliferative disorderThrombotic thrombocytopenic purpuraEstrogen treatmentHyperlipidemiaDiabetes mellitusHyperviscosityNephrotic syndromeCongestive heart failureParoxysmal nocturnal hemoglobinuria • Physiologic statesPregnancy (especially postpartum)ObesityPostoperative stateImmobilizationOld age
AFECTIUNI TROMBOTICE – CAUZE (2)
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TERAPIA
• ANTIAGREGANTĂ PLACHETARĂ
• ANTICOAGULANTĂ
• FIBRINOLITICĂ
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TERAPIA
• ANTIAGREGANTĂ PLACHETARĂ
• ANTICOAGULANTĂ
• FIBRINOLITICĂ
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TERAPIA ANTIAGREGANTĂ PLACHETARĂI. INHIBITORI DE COX
Acidul acetil salicilic (ASA) - Aspirina
II. INHIBITORI DE ADP
Ticlopidina – Ticlid
- Ticlopidina
- Ipaton
Clopidogrel - Plavix
III. INHIBITORI DE Gp IIb-IIIa – i.v.
Abciximab (Rheo-Pro)
Epifibatide (Integrilin)
Tirofiban (Aggrastat)
În studiu – fără a se fi dovedit beneficiul
clinic/avantaje• Sulfin-pirazonele
• Dipiridamolulul (inhibitor PDE)
• PGI2 (PC) – analogii PC
• Blocanţii TxA2-sintetază, antagoniştii de receptori de TXA2
• Inhibitori Gp IIb-IIIa cu administrare p.o.
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TERAPIA ANTIAGREGANTĂ PLACHETARĂ
ASA – cel mai studiat• inhib. COX plachetare = ireversibilă
endoteliale = reversibilă
– inhibă agregarea plachetară indusă de TxA2, nu şi de alţi agonişti
- efectul apare la doze : 160 mg/zi sau 325 mg/la 2 zile
Beneficii dovedite de studiile clinice
• SCA incidenta IMA primar (desi nu influenteaza frecv., intensit., durata crizelor anginoase
incidenta IMA secundar (25%)
nu e eficientă în menţinerea patenţei vasculare post stent, PTCA
Efect antiagregant plachetar
Efect antiinflamator ( - la dozele antiagregante)
• Protezaţii valvular incidenţa emboliei cerebrale
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TERAPIA ANTIAGREGANTĂ PLACHETARĂ
ASABeneficii dovedite de studiile clinice - continuare
• Boli cerebrovasculare ocluzive
incidenţa AIT ( + coumarine)
incidenţa AVC secundare
• IRA menţine patenţa canulelor aa. – vv. la dializaţi
progresia GN
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TERAPIA
• ANTIAGREGANTĂ PLACHETARĂ
• ANTICOAGULANTĂ
• FIBRINOLITICĂ
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TERAPIA ANTICOAGULANTĂ
HEPARINĂ (UF-conv., F-LMWH)
ANTIVITAMINE K (COUMARINE)
ACUTĂ
CRONICĂ
5 – 7 zile
• monitorizare : APTT
• monitorizare : PT (TQ), INR, IP
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HEPARINA - MPZ natural, agonist AT III (inhibă toţi FPC, cu excepţia F VII)
- generarea de T şi formarea de F
- împiedică formarea de noi trombi, nu lizează trombii preformaţi
• CONVENTIONALĂ (nefractionata- UF, cu Gm mare) Bolus iniţial de 5.000 – 10.000 u
PEV continuă
sau
s.c. / i.v.
doză suficientă să menţină APTT 1,5 – 2,5 x f.d. APTT
preheparină
800 – 1000 u / h
5000 u la 6 ore ( 4x / zi)
- Se menţine până la iniţierea terapiei ACO şi atingerea PT (TQ) ideal
– de obicei, 5-7 zile de suprapunere
- Extrem de heterogenă ca - activitate biologică (20%)
- Gm
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HEPARINA• LMWH ( H cu Gm mică, fracţionată)- mai scumpă f.d. UFH, dar AVANTAJE :
farmacocinetică previzibilă - nu necesită monitorizarea APTT
se poate administra s.c. 1x sau 2x / zi – ambulator
imunogenitate (incidenţa tr-citopeniei )
• DALTEPARINA (FRAGMIN) : 120 IU/kgc s.c. la 12 ore (2x /zi)
- Condiţionare : - fiole : 10.000 IU-antiXa / mL
- seringă monodoză 0,2 mL cu 2.500 IU antiXa
- seringă monodoză 0,2 mL cu 5.000 IU antiXa
- seringă monodoză 0,3 mL cu 7.500 IU-antiXa
- seringă monodoză 0,6 mL cu 15.000 IU-antiXa
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HEPARINA
• LMWH (fracţionată)
• ENOXAPARINA (Clexane)
– 100 IU antiXa = 1 mg / kgc s.c. la 12 ore ( 2x / zi)
- Condiţionare : - soluţie conţinând 10.000 IU antiXa = 100 mg / mL
- seringă monodoză 0,2 mL – 2000 IU antiXa = 20 mg
- seringă monodoză 0,4 mL – 4000 IU antiXa = 40 mg
- seringă monodoză 0,6 mL – 6000 IU antiXa = 60 mg
- seringă monodoză 0,8 mL – 8000 IU antiXa = 80 mg
- seringă monodoză 1 mL – 10.000 IU antiXa = 100 mg
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(Clexane)
1 mg = 100 IU
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Anticoagulant Therapy with Low-Molecular-Weight and Unfractionated Heparin
Clinical Indication Heparin Dose and Schedule
Target PTTa LMWH Dose and Scheduleb
Venous thrombosis pulmonary embolism
Treatment 5000 U IV bolus; 1000-1500 U/h
2-2.5 100 U/kg SC bid
Prophylaxis 5000 U SC q8-12h <1.5 100 U/kg SC bid
Acute myocardial infarction
With thrombolytic therapy
5000 U IV bolus; 1000 U/h
1.5-2.5 100 U/kg SC bid
With mural thrombus 8000 U SC q8h + warfarin
1.5-2.0 100 U /kg SC bid
Unstable angina 5000 U IV bolus; 1000 U/h
1.5-2.5 100 U/kg SC bid
Prophylaxis
General surgery 5000 U SC bid <1.5 100 U/kg SC before and bid
Orthopedic surgery 10000 U SC bid 1.5 100 U/kg SC before and bid
Medical patients with CHF, MI
10000 U SC bid 1.5 100 U/kg SC bid
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a Times normal control; assumes PTT has been standardized to heparin levels so that 1.5-2.5 x normal equals 0.2-0.4 U/mL; - if PTT is normal (27-35 S), start with 5000 U bolus 1300 U/h infusion monitoring PTT; - if PTT at recheck is <50 S, rebolus with 5000 U and increase infusion by 100 U/h; - if PTT at recheck is 50-60 s, increase infusion rate by 100 U/h; - if PTT at recheck is 60-85 s, no change;
- if PTT at recheck is 85-100 s, decrease infusion rate 100 U/h; - if PTT at recheck is 100-120 s, stop infusion for 30 min and decrease rate 100 U/h at restart;
- if PTT at recheck is >120 s, stop infusion for 60 min and decrease rate 200 U/h at restart.
b LMWH does not affect PTT and PTT is not used to adjust dosage.
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COMPLICAŢIILE HEPARINOTERAPIEI
• HEMORAGII (UFH, mai puţin LMWH)
- la nivelul suturilor chirurgicale
- în retroperitoneu
- ESTE INTERZISĂ INJECTAREA I.M. LA PTS. CARE FAC HEPARINOTERAPIE (mai ales UFH) sau TERAPIE ANTIAGREGANTĂ PLACHETARĂ
• dozei sau chiar oprirea administrării
• sulfat de protamină
• TROMBOCITOPENIE (UFH, mai puţin LMWH)
- apare la 10 % dintre pts.
- este uşoara : Nr. Pl. = 50.000 – 100.000 /μL
- heparina din plamân bovin >>> heparina din intestin de porc
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Mecanism : autoAC anti complex (UFH – factorul antiheparinic plachetar= PF-4) legare de receptorul Fc plachetar activare plachetară, aglutinare : tromboză arterială paradoxală
• Este esenţială recunoaşterea complicaţiei : întreruperea heparinoterapiei are efect reversibil şi este salvatoare pt. pacient
COMPLICAŢIILE HEPARINOTERAPIEI
• TROMBOCITOPENIE (UFH, mai putin LMWH) - continuare
- LMWH – sunt mai puţin imunogene, dar Ac rezultaţi din expunerea anterioară la UF pot da cross-reacţii cu LMWH
- LMWH – utile în trat. pts. cu tr.-citopenie
• OSTEOPOROZĂ (administrare > 5 luni)
- UFH >>> LMWH
Mecanism : activarea osteoclastelor
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ANTICOAGULAREA CRONICA CU AVK - COUMARINE
- generarea de T prin inactivarea FCP (II, VII, IX, X – PC, PS)
- Administrarea dozei de AVK şi monitorizarea PT (TQ) şi a INR, până la atingerea nivelului optim al anticoagulării, în funcţie de afecţiune
- deşi în câteva zile nivelul PT ajunge la ţinta propusă, stabilă a proteinelor
complexului PT necesită cel putin 1 săptămână de administrare de AVK
- odată atins nivelul ţintă al PT – terapie cronică (pe perioade variabile) cu monitorizarea PT (TQ), INR, IP
INR = International Normalised Ratio
- Tromboplastinele comerciale au potenţe extrem de variabile efort internaţional de standardizare a terapiei anticoagulante, indiferent de tipul de tromboplastină utilizat, de standardul fiecarui laborator
INR = ( PT pts. / PT normal) ISI
ISI = International Sensitivity Index
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INDICE DE PROTROMBINA (PI) vs. INR
PI = PT pacient / PT normal
- Tromboplastinele comerciale au potenţe extrem de variabile efort internaţional de standardizare a terapiei anticoagulante, indiferent de tipul de tromboplastină utilizat, de standardul fiecarui laborator
INR (International Normalized Ratio) (Raportul international normalizat)
INR = PT pacient / PT normal( )ISI
ISI = International Sensitivity Index
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INR Target Ranges for Oral Anticoagulation
Condition INR Duration
Venous thrombosis
Treatment 3 or > 3 3-6 months
Prevention 2-2.5 Chronic
Atrial fibrillation 2-32 ( > 75 yo)
Chronic
Myocardial infarction 2-3 2-3 months
Lupus-like anticoagulants 3-4 Chronic
Tissue valves 2-2.5 Chronic
Mechanical valves 3-4 Chronic
Cardiomyopathy 2-3 Chronic
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Effect of Drugs and Metabolic Changes on Oral Anticoagulant Potency
I. Factors leading to enhanced potency and increased prothrombin timeA. Reduced coumarin clearance1. Disulfiram2. Metronidazole3. Trimethoprim-sulfamethoxazoleB. Reduced albumin bindingPhenylbutazoneC. Additive hemostatic effect of certain drugs or disorders1. Aspirin2. Heparin3. Liver disease4. Thrombocytopenia5. Vitamin K deficiencyD. Increased turnover of vitamin K1. Clofibrate2. Hypermetabolism (e.g., hyperthyroidism)II. Factors leading to diminished potency and decreased prothrombin timeA. Accelerated coumarin clearanceæinduction of hepatic metabolizing enzymes1. Barbiturates2. RifampinB. Reduced absorptionCholestyramineC. Impaired metabolismGenetic coumarin resistance
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AVK
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COMPLICAŢIILE ANTICOAGULĂRII CU AVK
• HEMORAGII
- riscul tr-embolismului , în timp ce riscul hemoragiilor odată cu duratei tratamentului cu AVK
-pts. cu 1 episod tr-embolic necomplicat au beneficiu maxim la 3 – 6 luni de AVK
- în decurs de 1 an :
-10% din pts. anticoagulaţi prezintă un episod hemoragic ce necesită supraveghere medicală / spitalizare
- 0,5 – 1% prezintă hemoragie fatală
Trat. - dozelor / stop AVK
- plasmă proaspătă congelată – efect imediat / durează câteva ore
- administrarea VK – efect după 8 – 12 ore
- reinducerea anticoagulării dificilă
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COMPLICAŢIILE ANTICOAGULĂRII CU AVK
• NECROZA CUTANATĂ HEMORAGICĂ
- rară
- apare din cauza PC (mai ales la cei cu nivele congenital de PC ) administrarea de H şi plasmă proaspătă pentru refacerea nivelelelor PC
• REZISTENŢA LA COUMARINE – necesită doze
• INGESTIA VOLUNTARĂ DE COUMARINE
- Toxicologie : dozarea nivelului plasmatic al coumarinelor
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AVK
DabigatranPradaxa – Boehringer
Ingelheimoct. 2010
RivaroxabanXarelto - Bayer/Johnson &
Johnsonnov. 2010
Apixaban Eliquis - Pfizer/Bristol-
Myers SquibbAVERROESARISTOTLE
NOI ANTICOAGULANTE ORALE
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RE-LY: Cardiac events and net clinical benefit (rate per 100 person-years)
Events/benefit Dabigatran 110 mg Dabigatran 150 mg Warfarin All ischemic events 3.38 3.53 3.60Net clinical benefit 7.34 7.11 7.91
Net clinical benefit: Composite of stroke, MI, CV death, pulmonary embolism, systemic embolism, or major
bleeding
Meta-analysis: MI risk with dabigatran vs control
End point Dabigatran, n (%) Control, n (%) HR (95% CI) P MI incidence 237/20 000 (1.19%) 83/10 514 (0.79%) 1.33 (1.03-1.71) 0.03
Hohnloser SH, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY trial. Circulation 2012; DOI: 10.1161/?CIRCULATIONAHA.111.055970. Available at:
http://circ.ahajournals.org
PRECAUTII !!!!! – REZULTATE RECENTE
Uchino K, et al. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; DOI: 10.1001/archinternmed.2011.1666. Available at:
http://archinte.ama-assn.org/.
In trials comparing dabigatran and warfarin, there was a signal of increased MI
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TERAPIA
• ANTIAGREGANTĂ PLACHETARĂ
• ANTICOAGULANTĂ
• FIBRINOLITICĂ
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Possible Indications for Fibrinolytic Therapy
•Acute coronary occlusion•Acute peripheral arterial occlusion•Massive pulmonary embolism with severe hypoxemia and hypotension•Axillary vein thrombosis•Massive iliofemoral vein thrombosis efficacy as yet unproven•Occluded arterial or venous cannulae low dose, direct infusion into cannula•Venoocclusive disease of the liver
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Fibrinolytic Activators
Product Source Molecular Weight
Fibrin-Specific
Complications
Recombinant tissue plasminogen activator (rtPA)
Recombinant 70,000 + Bleeding
Pro-urokinase (proUK)
Melanoma cell cultures
55,000 + Bleeding
Urokinase (UK) Renal tubular cell cultures
33,000 - Bleeding
Streptokinase (SK)
b-Hemolytic streptococci
47,000 - Immune reactions (hypotension, fever)Bleeding
Acyl-SK-plasmin(ogen)
Chemical synthesis
139,000 +/- Immune reactions (hypotension, fever)Bleeding
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HAEMOSTASIS & THROMBOSIS